MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer.
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ABSTRACT:
SUBMITTER: Zhang GM
PROVIDER: S-EPMC4414271 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Project description:Background:Aberrant expression of CAV3.1, one of T-type Ca2+ channels, is reported to exert important functions in pathological processes, including carcinogenesis. However, its expression pattern and function in prostate cancer (PCa) remains unclear. Materials and methods:The expression pattern of CAV3.1 was analyzed in multiple ways, including online analysis in Oncomine database, experimental analyses in cell lines, and collected clinical specimens using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blot. Then, CAV3.1 was downregulated in PCa cells to explore its functions. Results:Upregulated CAV3.1 in PCa tissues and cells was confirmed by analyzing mRNA expression datasets from Oncomine and quantitative reverse transcription polymerase chain reaction detection, respectively. Accordingly, significantly higher CAV3.1 protein level in PCa tissues specimens than that in benign prostatic hyperplasia tissues was indicated by immunohistochemical staining. In addition, CAV3.1 upregulation was positively associated with metastasis. Depletion of CAV3.1 impaired the proliferation, migration, and invasion ability of PCa cells demonstrating by cell functional experiments, such as CCK-8, cell cycle distribution, plate clone formation, scratch wound healing, and transwell invasion assays. Mechanistically, due to constrained Akt activity, CAV3.1 knockdown resulted in decreased level of CCND1, N-cadherin, and Vimentin, and increased level of E-cadherin whose expressions could be reversed by ectopic Akt expression. Similarly, ectopic Akt expression also rescued the inhibitory effects of CAV3.1 knockdown on cell functions like proliferation and migration in PCa cells. Conclusion:Upregulated CAV3.1 is positively associated with the development of PCa. CAV3.1 knockdown can inhibit PCa cell proliferation, migration, and invasion by suppressing AKT activity.
| S-EPMC6197829 | biostudies-other
Project description:PBX/knotted 1 homeobox 2 (PKNOX2) has been implicated in tumorigenesis; however, its role in lung cancer (LC) remains unknown. The present study thus aimed to examine the expression, regulation, function and clinical implication of PKNOX2 in LC. A series of experiments were performed, including Cell Counting Kit-8 assay, cell cycle analysis, wound-healing assay, Transwell assay, methylation-specific PCR and western blotting. Bioinformatics analysis revealed that PKNOX2 was a LC-related gene, and a decrease in its expression was found in LC tissues from three public datasets. The results of reverse transcription-quantitative PCR assays also confirmed that PKNOX2 mRNA expression was markedly downregulated in LC tissues (n=60, P<0.01) and in five types of LC cell lines, and this was associated with the promoter methylation of PKNOX2. In addition, PKNOX2 expression was significantly associated with tumor invasion (P<0.0001), lymph node metastasis (P=0.0057) and TNM stage (P=0.0003); however, it was not associated with sex, age, pathological type or distant metastasis. The data obtained in vitro demonstrated that PKNOX2 silencing promoted LC cell proliferation and inhibited cell cycle arrest, accompanied by an increase in the expression levels of cell cycle-related proteins (cyclinD1, cyclinE1, CDK2 and CDK4), whereas PKNOX2 overexpression exhibited the opposite trend. In addition, PKNOX2 inhibited the migration and invasion of LC cells. Mechanistically, PKNOX2 knockdown activated the PI3K/AKT/mTOR signaling pathway by accelerating the phosphorylation of PI3K, AKT and mTOR, whereas PKNOX2 overexpression inactivated this signaling pathway. In conclusion, the findings of the present study suggested that PKNOX2 may suppress LC cell proliferation by inhibiting the PI3K/AKT/mTOR axis.
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Project description:BackgroundAberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells.MethodTo further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f cre+ Mig-6 f/f ). We examined P4 effect and regulation of AKT signaling in the endometrium of mutant mice.ResultsSprr2f cre+ Mig-6 f/f mice developed endometrial hyperplasia. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling and the restoration of stromal PGR and ESR1 expression. Furthermore, our in vitro studies revealed an inhibitory effect of MIG-6 on AKT phosphorylation as well as MIG-6 and AKT protein interactions.ConclusionsThese data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.
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Project description:MEX3A, one member of the human MEX3 gene family, exerts different effects on a variety of human cancer cells. However, the biological functions and regulatory mechanism have not been explored in cervical cancer. In our study, we used multiple approaches to determine the functions and underlying molecular mechanism of MEX3A in cervical tumorigenesis, including CCK-8 assay, BrdU assay, FACS for cell cycle and apoptosis, wound healing assay, Transwell migration and invasion assays, immunohistochemistry (IHC) assay, Transfection, real-time RT-PCR and Western blotting analysis. IHC results showed that the expression levels of MEX3A were decreased in cervical cancer patients with advanced clinical stages and lymph node involvement. Moreover, upregulation of MEX3A attenuated cell proliferation, migration and invasion and induced cell cycle arrest at G0/G1 phase in human cervical cancer cells, whereas knockdown of MEX3A exhibited the opposite effects. Mechanistically, MEX3A exerted its tumor suppressive functions via inactivation of Akt signaling pathway and inhibiting epithelial to mesenchymal transition (EMT). Importantly, Akt activation by its activator SC79 reversed the biological functions of MEX3A overexpression. Furthermore, MEX3A inhibited tumor growth in xenograft models. Overall, our investigation suggested that MEX3A participated in antitumor activity in cervical cancer by inhibition of the Akt signaling pathway and EMT. Hence, targeting MEX3A might have a therapeutic potential to treat cervical cancer.
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Project description:BackgroundEukaryotic initiation factor 3 (eIF3) is the largest translation initiation factor, and oncogenic roles have been discovered for its subunits, including the f subunit (ie, eIF3f), in various human cancers. However, the roles of eIF3f in the development and progression of prostate cancer (PCa) have not been reported.Materials and methodsWe performed in silico analysis to screen the expression of eIF3 subunits. Relevant shRNAs were used to knock down eIF3 subunits in 22Rv1 cells and cell proliferation was analyzed. eIF3f expression in PCa specimens was confirmed by immunohistochemistry. eIF3f knockdown was established to evaluate the effects of eIF3f on cell proliferation in vitro and in vivo. RNA-seq, bioinformatics analysis and Western blotting were applied to explore the molecular details underlying the biological function of eIF3f in PCa cells. shRNA-resistant eIF3f and myristoylated-Akt were used to rescue the effects of eIF3f disturbance on PCa cells.ResultsFunctional analyses confirmed that eIF3f is essential for PCa proliferation. Notably, the expression of eIF3f was found to be elevated in human PCa tissues as well as in PCa cell lines. eIF3f silencing significantly suppressed the growth of PCa cells, both in vitro and in vivo. eIF3f expression was positively correlated with Akt signaling activity in RNA-seq profiles and published prostate cohorts. Knockdown of eIF3f markedly reduced the levels of phosphorylated Akt in PCa cells. Exogenous expression of shRNA-resistant eIF3f in eIF3f knockdown cells restored Akt phosphorylation levels and cell growth. Importantly, rescue experiments revealed that ectopic expression of myristoylated-Akt partially alleviated the suppressive effects of eIF3f disturbance with respect to the growth of PCa cells.ConclusionThese results suggested that eIF3f has an oncogenic role in PCa, mediated at least partially through the regulation of Akt signaling, and that eIF3f represents a potential target for the inhibition of PCa growth and progression.
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Project description:A previous study reported the decreased expression of long non-coding RNA mortal obligate RNA transcript (lncRNA MORT) in 16 types of cancer, while the functionality of lncRNA MORT in cancer biology remains unknown. Therefore, the present study was conducted to characterize the functionality of lncRNA MORT in prostate carcinoma, a common cancer type worldwide. lncRNA MORT expression level was downregulated in tumor tissues compared with that in the adjacent healthy tissues of patients with prostate carcinoma. Expression of lncRNA MORT in tumor tissues was influenced by tumor size, but not by tumor metastasis. Overexpression of lncRNA MORT inhibited glucose uptake and glucose transporter 1 (GLUT-1) expression in prostate carcinoma cell lines; GLUT-1 overexpression upregulated glucose uptake and attenuated the effects of lncRNA MORT overexpression on glucose uptake, but did not significantly affect the expression of lncRNA MORT. Overexpression of lncRNA MORT inhibited, while GLUT-1 overexpression promoted the proliferation of prostate carcinoma cells. In addition, GLUT-1 overexpression attenuated the effects of lncRNA MORT on cell proliferation. Therefore, lncRNA MORT may inhibit cancer cell proliferation in prostate carcinoma by preventing glucose uptake.
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Project description:The consumption of foods containing resveratrol produces significant health benefits. Resveratrol inhibits cancer by reducing cell proliferation and metastasis and by inducing apoptosis. These actions could be explained by its ability to inhibit (ERK-1/2), Akt and suppressing the levels of estrogen and insulin growth factor -1 (IGF-1) receptor. How these processes are manifested into the antitumor actions of resveratrol is not clear. Using microarray studies, we show that resveratrol reduced the expression of various prostate-tumor associated microRNAs (miRs) including miR-21 in androgen-receptor negative and highly aggressive human prostate cancer cells, PC-3M-MM2. This effect of resveratrol was associated with reduced cell viability, migration and invasiveness. Additionally, resveratrol increased the expression of tumor suppressors, PDCD4 and maspin, which are negatively regulated by miR-21. Short interfering (si) RNA against PDCD4 attenuated resveratrol's effect on prostate cancer cells, and similar effects were observed following over expression of miR-21 with pre-miR-21 oligonucleotides. PC-3M-MM2 cells also exhibited high levels of phospho-Akt (pAkt), which were reduced by both resveratrol and LY294002 (a PI3-kinase inhibitor). MiR-21 expression in these cells appeared to be dependent on Akt, as LY294002 reduced the levels of miR-21 along with a concurrent increase in PDCD4 expression. These in vitro findings were further corroborated in a severe combined immunodeficient (SCID) mouse xenograft model of prostate cancer. Oral administration of resveratrol not only inhibited the tumor growth but also decreased the incidence and number of metastatic lung lesions. These tumor- and metastatic-suppressive effects of resveratrol were associated with reduced miR-21 and pAkt, and elevated PDCD4 levels. Similar anti-tumor effects of resveratrol were observed in DU145 and LNCaP prostate cancer cells which were associated with suppression of Akt and PDCD4, but independent of miR-21.These data suggest that resveratrol's anti-tumor actions in prostate cancer could be explained, in part, through inhibition of Akt/miR-21 signaling pathway.
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Project description:BACKGROUND:Signal regulatory protein β1 (SIRPB1) is a signal regulatory protein member of the immunoglobulin superfamily and is capable of modulating receptor tyrosine kinase-coupled signaling. Copy number variations at the SIRPB1 locus were previously reported to associate with prostate cancer aggressiveness in patients, however, the role of SIRPB1 in prostate carcinogenesis is unknown. METHODS:Fluorescence in situ hybridization and laser-capture microdissection coupled with quantitative polymerase chain reaction was utilized to determine SIRPB1 gene amplification and messenger RNA expression in prostate cancer specimens. The effect of knockdown of SIRPB1 by RNA interference in PC3 prostate cancer cells on cell growth in colony formation assays and cell mobility in wound-healing, transwell assays, and cell cycle analysis was determined. Overexpression of SIPRB1 in C4-2 prostate cancer cells on cell migration, invasion, colony formation and cell cycle progression and tumor take rate in xenografts was also determined. Western blot assay of potential downstream SIRPB1 pathways was also performed. RESULTS:SIRPB1 gene amplification was detected in up to 37.5% of prostate cancer specimens based on in silico analysis of several publicly available datasets. SIRPB1 gene amplification and overexpression were detected in prostate cancer specimens. The knockdown of SIRPB1 significantly suppressed cell growth in colony formation assays and cell mobility. SIRPB1 knockdown also induced cell cycle arrest during the G0 /G1 phase and enhancement of apoptosis. Conversely, overexpression of SIPRB1 in C4-2 prostate cancer cells significantly enhanced cell migration, invasion, colony formation, and cell cycle progression and increased C4-2 xenograft tumor take rate in nude mice. Finally, this study presented evidence for SIRPB1 regulation of Akt phosphorylation and showed that Akt inhibition could abolish SIRPB1 stimulation of prostate cancer cell proliferation. CONCLUSIONS:These results suggest that SIRPB1 is a potential oncogene capable of activating Akt signaling to stimulate prostate cancer proliferation and could be a biomarker for patients at risk of developing aggressive prostate cancer.
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Project description:ADAR (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to generate inosine, through its binding to double-stranded RNA (dsRNA), a phenomenon known as RNA editing. One of the functions of ADAR1 is suppressing the type I interferon (IFN) response, but its mechanism in gastric cancer is not clearly understood. We analyzed changes in RNA editing and IFN signaling in ADAR1-depleted gastric cancer cells, to clarify how ADAR1 regulates IFN signaling. Interestingly, we observed a dramatic increase in the protein level of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 9 (IRF9) upon ADAR1 knockdown, in the absence of type I or type II IFN treatment. However, there were no changes in protein expression or localization of the mitochondrial antiviral signaling protein (MAVS) and interferon alpha and beta-receptor subunit 2 (IFNAR2), the two known mediators of IFN production. Instead, we found that miR-302a-3p binds to the untranslated region (UTR) of IRF9 and regulate its expression. The treatment of ADAR1-depleted AGS cells with an miR-302a mimic successfully restored IRF9 as well as STAT1 protein level. Hence, our results suggest that ADAR1 regulates IFN signaling in gastric cancer through the suppression of STAT1 and IRF9 via miR-302a, which is independent from the RNA editing of known IFN production pathway.
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Project description:Prostate cancer (PCa) is prevalent among older men and difficult to survive after metastasis. It is urgent to find new drugs and treatments. Several studies show that taraxasterol (TAX) has important anti-inflammatory, anti-oxidative and anti-tumor effects. However, the function and mechanisms of TAX in PCa remain unclear. Here, we found that TAX could significantly suppress the viability and growth of androgen-independent PCa cells and down-regulate the expression of c-Myc and cyclin D1 in vitro. Mechanistically, PI3K/AKT signaling pathway was weakened and the expression of FGFR2 was reduced after TAX treatment in androgen-independent PCa cells. Moreover, TAX evidently inhibited the tumor growth in nude mice and the expression of c-Myc, cyclin D1, p-AKT and FGFR2 were down-regulated in xenograft tumor. These results indicate that TAX suppresses the proliferation of androgen-independent PCa cells via inhibiting the activation of PI3K/AKT signaling pathway and the expression of FGFR2, which means TAX may be a novel anti-tumor agent for later PCa treatment.
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